FI79115C - FOERFARANDE FOER FRAMSTAELLNING AV 1-ETOXIKARBONYLOXIETYLESTERN AV 6- (D - (-) - -AMINO- -PHENYLACETAMIDO) PENICILLANSYRA. - Google Patents

Description

1 79115

Process for the preparation of 6- (D - (-) - <X-amino-O-phenyl-acetamido) penic acid 1-ethoxycarbonyloxyethyl ester

The present invention relates to a new process for the preparation of 1-ethoxycarbonylloxy ethyl 6- (D- <-> - (N-amino-phenyl) acetamido) penicillanic acid ethyl ether of the formula CHq / CH-CO-NH-CH-CH C ( I) III lx-3 NH2 CO - N-CH - C00 - CH - 0 - COOC2H5 ch3

Said compound I is an ampicillin ester which is very important from a therapeutic point of view because it is well absorbed when administered orally and provides much higher concentrations of ampicillin in the blood than the ampicillin itself.

This ester is separated in the form of the hydrochloride and is called bacampicin hydrochloride.

Based on previously known methods (cf. BE patent 772,723), bacampicin hydrochloride can be prepared synthetically by the following two methods: A) By reacting potassium benzylpenicillin with 1α-chloride-ethyl carbonate in organic solvents or dioxane in 70% water: in the presence of sodium bicarbonate. The 1-ethoxycarbonyloxyethyl ester of benzylpenicillin, which is then obtained, is subjected to a reaction in which the phenylacetic acid chain is removed by means of an iminochloride iminoether in order to obtain 6-aminopememenylic acid 1-ethoxycarbonyloxyethoxyethyl ester,

2 79115

Subsequent condensation of the latter intermediate with D- <-> -o <-phenylglycine provides a compound of formula I.

B) By carrying out an esterification reaction of 6- (D- <-) - O (α t s i do-Df-phenyl) i as e t thamido) penicillanic acid with <X ~ chlorodiethyl carbonate in a polar solvent.

The compound of formula I is then obtained by catalytic hydrogenation of 6-(D- (-) - O-azido-Of-phenylacetamido) penicillanic acid 1-ethoxycarbonyloxy ethyl ester.

As can be seen, these methods are very complex because they involve the use of several raw materials and long processing times.

In addition, a process for the preparation of bac ampicinin is known from FI patent specification 55,203. In Example 16b of this patent, bacampicin is prepared by reacting 1-ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid with enamine-protected Of-aminophenylacetic acid. The yield of bakampicillin hydrochloride in this example is 0.35 g, corresponding to 7% based on the amount of 6-aminopenicillanic acid ester.

It is an object of the present invention to provide a process for the preparation of the active compound in question which is easier to carry out and more industrially advantageous. A more specific object of the invention is to provide a process for the preparation of bacampicin using ampicillin as a starting material by considerably simplifying said process to obtain the desired product in high purity.

The invention therefore relates to a process for the preparation of 6- [D - (-> - ° <-amino-of-phenylacetamidolpenicillanic acid 1-ethoxy] carboxylic acid ester of formula 3 79115 ch3 σΟΗ - CO - NH - CH - CH ^ C ^^ <I> II! IX ° H3 NH2 CO - N-CH - COO - CH - O - COOC2H5 ch3 by reacting ampicin, preferably in the form of an alkali salt, with a reactive derivative of acetoacetic acid to form the corresponding majority of formula / S \ S ™ 3 ('V-CH - CO - NH - CH -CH NC (II) N = r ||| lXc „3

N. CO - N-CH - COOX

1 X \

R-C H

i i 2 i R-C \ X ° I 3

R

1 2 wherein R is an alkyl group having 1 to 4 carbon atoms, R is a hydrogen or alkyl group having 1 to 4 carbon atoms, R is an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms or an amino group, and X is an alkali metal, earth -alkali metal or organic base, characterized in that the intermediate of formula II obtained is reacted with α-bromodiethyl carbonate of formula

Br-CH-O-C00C2H5 (III) ch3 in the presence of a catalyst to form the corresponding ester of formula 4 79115 β ~ \ / \

(/ ') - CH - CO - NH - CH - CH (T

| I | ^ ch3 1 / \ CO - N- · 0Η-000-σΗ-0-00002Η5 R-'C H CH,

R-C O

\ / C <IV)

I 3 R

Wherein R, R and R are as defined above, followed by careful hydrolysis in an acidic medium in a manner known per se to form a compound of formula I.

CX-br Omid i e type 1 rbonaa 11 ia is used as a reactant in the esterification treatment. The use of tx-bromide diethyl carbonate gives a very high yield and a very high purity of bakampin sline.

The esterification reaction between compounds II and III is carried out in the presence of an esterification catalyst.

The addition of the catalyst at this stage considerably shortens the reaction times and results in high product yields as well as a higher degree of purity.

For this purpose, the following compounds can be used as catalysts: quaternary ammonium salts, for example tetrabutylammonium bromide, bromides and iodides and cyclic ethers.

The catalyst can be used in an amount ranging from 0.005 to 0.10 moles per 1 mole of the compound of formula III, up to amounts equimolar with the compound III. In a preferred embodiment, tetrabutylammonium bromide is used in an amount of 0.01 to 0.10 moles per 1 mole of compound III.

1 2 3

Illustrative examples of R, R and R are as follows. : alkyl: CH 9, n-C 3 Hy, i-C g Hy, n-C 1 H 3 alkoxy <R only): OCH 9, OC 2 H 5, OCl 2 Cl 2 CH 2, OCH (CH 2> 2.

0 <CH2> 3CH3

Radical X is selected from groups well known in the art, such as:

time 1 imet a 11i: Na, K

alkaline earth metal 11 Ca: Mg organic bases: organic bases known from the synthesis of penicillins, for example tertiary amino groups, triethylamine, ethylpiperidine and methyl-1-morpholine.

In a preferred embodiment of the invention is the group protecting the amino group of ampicillin, the 1-methoxycarbonyl-propen-2-yl group or the 1-ethoxycarbonyl-propen-2-yl group, wherein the most preferred intermediate of formula II is N- (1-methoxy). sodium or potassium salt of -carbonyl-propen-2-yl) penicillanic acid and N- (1-ethoxycarbonylpropen-2-yl) penicillanic acid, respectively (R = methyl; R = methyl; R = methoxy) or ethoxy, and X = Na or K).

Intermediate IV is stable in a neutral or alkaline medium, while in an acidic medium it is possible to deprotect the amino group simply, rapidly and selectively.

The amino protecting group of ampicillin can be selected, for example, from those mentioned in GB Patent Publication No. 991,586 and other groups well known in the art.

6 79115

More specifically, a process according to a preferred embodiment of the invention comprises the steps of: converting ampicillin trihydrate in a polar solvent, e.g. N, N-dimethylformamide, to a salt, e.g. potassium salt, and then reacting the corresponding enamine (II) with an acetoacetic acid derivative, e.g. methylacetate; addition of an esterification catalyst, preferably tetrabutylammonium bromide; Addition of O (bromide ethyl carbonate) to the reaction mixture to form the 1-ethoxycarbonyl oxylethyl ester of ampicillin in the form of enamine (IV); hydrolysis of the protecting group with HCl diluted as an organic solvent, for example n-butyl acetate / water; bacampylin recovery of the hydrochloride by saturating the aqueous phase with, for example, sodium chloride and extracting with a suitable solvent such as n-butyl acetate, concentrating the solution under reduced pressure in n-butyl acetate in order to crystallize the product to very pure, whereupon this product is separated by filtration.

Among the main advantages of the process according to the invention, the most important is that with this process it is possible to obtain bakampicillin-1-hydrochloride in practically one treatment and in very pure form.

In reality, the impurities present in the product obtained by the process according to the invention are negligible in comparison with the previously known processes.

Another important advantage is that the starting material is am-pisl 111 nitrite, which is a known antibiotic and is easily obtained in pure form and at low cost.

7 79115 Intermediate (II) can be readily prepared as described, for example, in GB 991 5-6, in more than 95% yield by reacting ampicillin trihydrate with methyl or ethyl acetoacetate using this 10-50% higher amount than the stoichiometric amount of organic base or in the presence of an alkali metal carbonate such as potassium carbonate.

Intermediate (II) can be isolated and added by reaction. in solid form. Without isolating intermediate (II), the etherification reaction can be carried out in the same solvent as the enamine (II) formation reaction.

The reaction for the preparation of ampicillinamine (II) is carried out in an aprotic, polar solvent such as N, N-dimethylacetamide, N, N-dimethylformamide, dimethoxyethane, dimethyl sulfoxide, tetrahydrofuran or dioxin.

In order to complete the reaction, it is sufficient to keep the components of the mixture in contact with each other at a temperature between 0 and 60 ° C, preferably between 20 and 30 ° C, for 2 to 2 hours, preferably for 3 hours.

The etherification reaction takes place after the addition of cK-bromide diethyl carbonate to this mixture at a temperature between 15 and Θ0 ° C, preferably between 45 and 55 ° C, for 1 to 24 hours, preferably 5 to 10 hours.

The etherification reaction is conveniently carried out in an organic solvent such as methylene chloride or acetone, dimethylacetamide, dimethylformamide or dimethylsulfoxide, or a mixture of organic solvents. It is also possible to use an aqueous organic solvent. The use of an etherification catalyst is desirable when using acetone as the solvent for the esterification reaction.

8 79115

For the easiest and most suitable conditions, for industrial purposes, the esterified enamine (IV) is separated by diluting the reaction mixture with water and then extracting as a suitable solvent which is immiscible with water, for example n-butyl acetate.

The acetate phase is stirred with a dilute solution of HCl (0.2-0.3 N) until the protecting group is completely hydrolysed, which requires 2-8 hours, preferably 4-5 hours, of contact at normal temperatures.

Upon addition of sodium chloride, compound (I) separates from the error phase in the form of the hydrochloride, which is extracted with a suitable solvent, for example n-butyl acetate.

Upon concentration of the organic phase at low pressure at 40 ° C until the volume is small, crystallization of the compound of formula (I) takes place.

The crystallized product is separated by filtration, washing and drying in vacuo.

In this reaction, the carboxylic acid salt of formula II is reacted with b (bromodiethyl carbonate).

The reaction of metal salts of carboxylic acids with alkyl halides or aryl alkyl halides to form esters is well known. However, the yields are not very high and the reaction usually requires strong conditions such as high temperatures and / or long reaction times. Such conditions limit the synthetic utility of the reaction and its commercial utility with respect to heat-sensitive and labile substances such as pyrethroids, prostaglandins, peptides, penicillins, and cephalosporins.

3 79115 GB 1 443 733 discloses the use of a quaternary ammonium salt of penicillins and cephalosporins instead of their metal salt in the preparation of ethers of penicillins and cephalosporins.

The preparation of the quaternary ammonium salt of the acid can be time consuming and expensive. However, as also disclosed in GB 1 443 73Θ, it is necessary to first prepare a quaternary ammonium salt of penicillin or cephalosporin, but the reaction can be carried out by introducing a metal salt of a carboxylic acid, i. 6 -pa, penicillin or cephalosporin, to react with an alkyl or arylalkyl halide in the presence of a quaternary ammonium salt other than a carboxylic acid salt.

According to the invention, it has now been found that it is not necessary to use said quaternary ammonium salt in a stoichiometric amount of a carboxylic acid, i. ampicillin, but that less than an ethiometre of ampicillin is sufficient.

The invention thus provides a process for the preparation of the ethoxycarbonyloxyethyl ester of ampicillin by reacting a metal salt of protected ampicillin with α-bromodiethyl carbonate in the presence of a quaternary ammonium salt (other than the said carboxylic acid salt).

According to the invention, 1-25% of 1 equivalent of a quaternary ammonium salt are used for each equivalent of the metaboliser of carboxylic acid, and even more preferably 1-10% of the equivalent amount of quaternary ammonium salt.

10,791 1 5

The quaternary ammonium salt of a carboxylic acid is suitably prepared by reacting a metal salt of a carboxylic acid with a quaternary ammonium salt of an acid other than said carboxylic acid, usually using a mineral acid such as hydrochloric, hydrobromic or sulfuric acid.

Suitable metal salts of carboxylic acids which can be used according to the invention (either as precursors of the quaternary ammonium salt of carboxylic acid or as such) include alkali metal and alkaline earth metal salts such as sodium, potassium, lithium, magnesium and calcium salts. Suitable non-carboxylic acid quaternary ammonium salts (which can be used either as a precursor of quaternary ammonium salts of carboxylic acids or as such) include, for example, tetraalkylammonium salts such as tetra-n-butyl-ammonium bromide and cetyltrimethylammonium bromide, and quaternary trimethylammonium bromide, and Suitable halides include fluorides, chlorides, bromides and iodides, preferably activated fluorides and activated chlorides or bromides or iodides.

The esterification reaction according to this embodiment of the invention can be carried out in the presence or absence of a solvent. Examples of suitable solvents are lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic amides of formic acid and dimethyl sulfoxide. Alternatively, when no solvent is used, an excess of ester-forming halide may be used, especially if this is a liquid at the reaction temperature.

Approximately equimolar quaternary carboxylic acid ammonium salts and ester-forming ot-bromide diethyl carbonate can be used in the esterification reaction. Preferably a 5-100% excess of ester-forming ° (bromo-diethyl carbonate per equivalent of carboxylic acid salt is used), and more preferably this excess is 20-60%.

11 79115

The compound of formula III bromodiethyl carbonate is a novel compound and can be prepared by reacting the corresponding α-chloroethyl carbonate with sodium bromide as shown in Example 1 below.

The α-bromodiethyl carbonate of formula III can also be prepared by the following methods A and B.

A. The first of these methods, Method A, comprises the steps of: (a) reacting an aldehyde of formula CH 3 CHO <VI) with carbonyl bromide COBr 2 (VII) to give the -bromo-bromo formate of formula

Br CH3-CH.O.CO.Br (VIII) and (b) reacting the α-bromo-bromo formate of formula VIII with an alcohol of formula C2Hg-OH to give the desired α-bromo-diethyl carbonate of formula III.

Method A can be represented by the reaction scheme: pr + C2H5OH Br CH3CHO + COBr2-> CH3 - CH.O.CO.Br -> CHg - CH.0.CO.C2H5 + HBr

The α-bromo-bromo formate 11i of formula VIII is in itself a novel compound.

i2 791 1 5

The reaction between the aldehyde CH 2 CHO and the carbonyl bromide is preferably carried out in the presence of a catalyst which may be, for example, a tertiary amine (for example a tertiary aliphatic amine, a tertiary mixed alkyl / arylamine or a tertiary aromatic amine or a tertiary amine phosphine thiourea, phosphoric acid amide, tertiary oxonium or sulfonium salt or quaternary ammonium or phosphonium salt. Preferred examples of catalysts that can be used in Process A include pyridine, dimethylformamide, tetra-n-butylurea, hexamethylphosphoric acid trlamide and benzyltrimethylammonium bromide.

The catalyst is suitably used in amounts of 0.05 to 0.5, preferably 0.05 to 0.15 moles per 1 mole of aldehyde.

The reaction between the aldehyde and the carbonyl bromide is suitably carried out in the presence of a solvent which may be, for example, an aromatic hydrocarbon such as toluene or a halogenated hydrocarbon such as dichloromethane, carbon tetrachloride or chlorobenzene. The reaction between the aldehyde and the carbonyl bromide is suitably carried out at a temperature between -40 and + 120 ° C, o preferably 0-40 ° C. The carbonyl bromide is usually used in a molar excess relative to the aldehyde, with a suitable molar excess of 10-100%, preferably 20-50%.

The intermediate of formula VIII, α-bromo-bromo-formate, prepared in step A <a) of method A, does not need to be separated prior to reaction with the alcohol C 9 H 2 OH, and it is generally preferred not to do so. According to a preferred embodiment, the reaction mixture obtained in step (a) is liberated from the excess carbonyl bromide, for example by heating under reduced pressure or purging with nitrogen. The crude N-bromo-bromoformate-containing reaction mixture is then reacted with an amount of alcohol. The reaction may conveniently be effected by heating the mixture to reflux until the evolution of hydrogen bromide is complete, or by adding a tertiary base to the mixture and, if necessary, heating it. Any catalyst residue from step (a> or a complex thereof with carbonyl bromide does not appear to affect the next reaction and in some cases appears to be preferred.

The crude CX bromocarbonate obtained can be conveniently separated from the reaction mixture by fractional crystallization under reduced pressure.

Method A is described in Examples 2 and 3.

B. Another method, Method B, for preparing CX bromide diethyl carbonate is described below. Method B is shown in Example 4.

Method B relates to improvements in the preparation of O-bromodiethyl carbonate by modifying the Pinkelstein reaction, i. using the reaction of an alkyl chloride or an aryl or alkyl (or a compound containing such a group) with a bromide or an iodide to replace the chloro substituent with a bromo or iodine substituent, respectively, or using an alkyl bromide or an arylalkyl group compound) with an alkali metal iodide such that the bromo substituent is replaced by an iodine substituent.

The Finkelstein reaction is useful because the iodides obtained are generally more reactive than bromides, which in turn are more reactive than chlorides. In a few cases, only a catalytic amount of alkali metal bromide or iodide is required, and the resulting more reactive products are reacted with the desired substrate, which regenerates the early metal bromide or iodide and thus continues the reaction.

i4 79 1 1 5

Not all optionally substituted alkyl chlorides or arylalkyl clones undergo this reaction, and it has been found particularly difficult to carry out this reaction using α-chloroesters and O-chlorocarbonates and, i. compounds in which the chlorine atom is attached to a carbon atom which in turn is attached to either end of the group -C <O) -O-. An example of such a chlorocarbonate is O-chlorodiethyl carbonate, a known intermediate in the preparation of ethoxycarbonyloxyethyl esters of 6-aminopenic acid and penicillins, as described above.

This problem can be avoided by carrying out the reaction using a two-phase solvent system in which the second phase is water and the second is a water-immiscible organic solvent in the presence of a phase transfer catalyst.

Suitable water-miscible organic solvents which can be used according to the invention are halogenated hydrocarbons, for example halogenated paraffins, such as dichloromethane, and aromatic hydrocarbons, such as toluene. Suitable phase transfer catalysts include quaternary ammonium salts, for example tetraalkylammonium salts such as cetyltrimethylammonium bromide and tetra-n-butylammonium hydrogen sulphate. The time 1 sucked 111 bromide may be, for example, sodium, potassium or 1 lithium bromide, of which 1 lithium bromide is most preferred.

Thus, in Method B, o <-chlorodiethyl carbonate of the formula is obtained

Cl 0

I II

CHg -CH-O-C-O-C2H5 (IX) to react in a two-phase solvent system, one phase of which is water and the other of which is a water-immiscible organic solvent, with a bromide of formula 15 79 1 1 5 R-Br (X)

In which R is an alkali metal such as Na, K and Li to form a compound of formula

Br 0 J 11 ch3 -ch-o-c-o- C2H5 (III)

As mentioned above, the most preferred alkali metal R is Li, so LiBr is your most preferred reagent of formula X.

In connection with method B, it has been found that lithium bromide can be advantageously used in a conventional Finkelstein reaction (i.e. using a single-phase organic solvent system), for example by halogenating cX chlorocarbonate. This method is shown in Example 5.

Suitable solvents for such a process include lower aliphatic alcohols, lower aliphatic ketones, lower aliphatic ethers and lower aliphatic formic acid amides.

The following examples illustrate the invention. Examples 1-6 illustrate the preparation of a starting material of formula III and Example 7 illustrates the process of the invention.

Example 1 Preparation of α-bromide diethyl carbonate in acetone

NaBr + C1 -CH-OCOOC2H5- ^ Br-CH-OCOOC2H5 + NaCl ch3 ch3 16,791 1 5

Sodium bromide (102.9 g) dissolved in acetone (600 ml) was reacted for 2-3 hours at ambient temperature (20-25 ° C) with o-chlorodiethyl carbonate (152.6 g) dissolved in 100 ml of acetone. The mixture was then concentrated in vacuo at low temperature, max. 35 ° C, therefore until a semi-solid mass was obtained. The reaction mixture was then partitioned between Η20: η and ethyl ether. The aqueous phase was separated and then extracted twice with 400 ml of ethyl ether.

The combined organic phases containing o (bromodiethylcarbonate) were washed with: ΘΟΟ ml of H 2 O, 1000 ml of 1% aqueous sodium metabisulphate solution, 1000 ml of saturated NaCl solution.

The organic phase was dried over Mg sulphate and then concentrated in vacuo at low temperature, max. 35 ° C to give the title compound (60%) as a liquid which was initially colorless or slightly yellowish brown. It was used directly in the esterification step of Example 7.

Example 2

A mixture of acetaldehyde (44 g; 1 mol), carbon tetrachloride (300 ml) and freshly distilled carbonyl bromide (235 g; 1.25 mol) was cooled to 0 ° C and kept at this temperature with external cooling while ridine (11.9 g; 0.15 mol) was added over 1 hour.

The mixture was allowed to warm to ambient temperature and then heated to 50 ° C and kept at this temperature for 3 hours during which time a precipitate formed.

o

Evaporation of the reaction mixture under reduced pressure at 50 ° C gave a semi-solid, oily mass which readily dissolved in 17,791 l of ethanol (92 g; 2 moles) under heating and heating under reflux. After further heating at reflux for 2 hours, excess ethanol was removed in vacuo and the residue was triturated with water (100 mL) and methylene dichloride (200 mL).

Separation of the organic layer and fractional distillation gave pure ethyl OC-bromoethyl carbonate <130 g; yield o 66%), b.p. was 90-92 ° C at 45 mmHg and identical in all respects to the authentic sample.

Example 3

Mixture of acetaldehyde <44 g; 1 mol), dichloromethane <300 ml) and hexamethylphosphoric acid triamide <17.9 g; o 0.1 mol), cooled to -10 ° C and freshly distilled carbonyl bromide (207 g; 1.1 mol) was gradually added over 4 hours, during which time the temperature o was allowed to rise to 10 ° C.

The mixture was then gently heated to reflux (about 40 ° C) for 4 hours. While still refluxing, ethanol <69 g was carefully added; 1.5 moles) within 1 hour and heating at reflux was continued for another 1 hour.

Fractional distillation of the resulting mixture gave pure ethyl Oi-bromoethyl carbonate <114 g; yield 58%).

The authenticity of the ethyl <X-bromoethyl carbonate formed was confirmed by analysis and separate synthesis as follows.

Diethyl carbonate <118 g; 1.0 mole) was stirred and heated to a temperature between 110 and 120 ° C and irradiated with a 150 watt vo1 f ram wire lamp. Bromine <96 g; 0.6 moles) was added dropwise over 3-4 hours at such a rate that the mixture did not acquire a darker than light orange color.

ιβ 79115

When the addition of bromine was complete, the mixture was cooled to ambient temperature and sodium bicarbonate (20 g) was added.

Distillation and fractionation of the mixture gave authentic ethyl O-bromoethyl carbonate (84.2 g; 70% yield), b.p. 87-88 ° C at 40 mmHg.

Example 4

A mixture of lithium bromide (43 g; 0.5 mol), ethyl O (chloroethyl carbonate <15.3 g; 0.1 mol), water (100 ml), dichloromethane (100 ml) and cetyltrimethylammonium bromide (1 , 5 g), stirred at ambient temperature for 24 h. The aqueous layer was removed and replaced with 1 L of fresh lithium bromide solution <26 g; 0.3 mol) in water (40 ml) containing cetyltrimethylammonium bromide (1 g). After stirring for a further 24 hours, during which time the temperature rose to 35 ° C, the organic layer was separated, dried and distilled in vacuo to give, after repeated fractionation, a new compound, o-1f-br-Omie ty 1 i carbonate 15.0 g (yield 76%), b.p. was 90-92 C at 35 mmHg.

Found: C 30.7, H 4.8, Br 40.1%

Calculated: C 30.5, H 4.6, Br 40.6% The NMR spectrum had the following peaks: 1.2-1.6 <3H, triple band) -CHo.CH 2 2.0-2.2 <3H, double band ) -CH .QM3 4.1- 4.5 <2H, four-line) -CHoCHg 6.5-6.8 (1H, four-line) -CH.CHg

Example 5

Lithium bromide (17.4 g; 0.2 mol) was dissolved in dimethylformamide (150 ml) and the mixture was cooled to ambient temperature. Ethyl i-carbonate (30.5 g; 0.2 mol) was added and the mixture was stirred at ambient temperature for 24 h.

19 79115

The precipitated lithium chloride was filtered off and the filtrate was distilled in vacuo to give, after careful re-fractionation, ethyl iO-O-brominated carbonate and 76% yield based on the recovered ethyl i-OC-chloro-ethyl carbonate.

Example 6

The authenticity of the above-mentioned new compound, e ty 1 i - <Y-br omi e t yy 1 age r bonate, was separately confirmed by synthesis from the following:

A mixture of diethyl carbonate <35 g; 0.3 mol) in carbon tetrachloride (50 ml) and O <-azoleobutyronitrile (ATBN) <0.1 g), was gently heated under reflux, and dibromo-dimethylhydantoin <28.6 g; 0.1 mol) was added in small portions over 8 hours along with an additional amount of AIBN (8 x 0.05 g). Care was taken not to accumulate free bromine in the reaction mixture. At the end of the reaction, the mixture was subjected to vacuum fractions to give pure ethyl-O (O-bromoethyl] carbonate <32.3 g; yield 82%), which was identical in all respects to the products of Examples 4 and 5.

Example 7 25.08 g (0.181 mol) of finely ground anhydrous potassium carbonate was euspended in 200 N, N-dimethylacetamide and 32.4 ml (0.3 mol) of methyl acetoacetate and 60.4 g (0.15 mol) were added. ) ampisiene trihydrate.

The mixture was stirred vigorously for 5 hours at 20 DEG-25 DEG C. and then 46.1 g (<0.234 mol) of bromide ethyl carbonate, 6 g (0.02 mol) of tetrabutylammonium bromide and 100 ml of N, N-dimethylacetamide were added.

The mixture was heated with stirring for 10 hours at 40-42 ° C, and the reaction mixture was poured into a mixture of 1200 ml of water and 400 ml of n-butyl acetate.

20 79 1 1 5

The aqueous phase was collected and extracted with a further 100 ml of n-butyl acetate.

The recombined organic phases were washed twice with 100 ml of water. 150 ml of 1N HCl and 370 ml of water were added to the organic phase with stirring, and stirring was continued for 10 hours at 22-23 ° C.

The aqueous phase was collected and the organic phase was extracted with 100 ml of water.

The combined aqueous phases were adjusted to pH 4 with 10% aqueous Na 2 CO 0, then bleaching carbon was added and the mixture was filtered.

To the aqueous filtrate were added 300 ml of n-butyl acetate and Θ0 g of sodium chloride.

The organic phase was separated and the aqueous phase was extracted with 200 ml of n-butyl acetate.

The combined phases were concentrated in n-butyl acetate under reduced pressure at 40 ° C to a volume of about 300 ml. The product o was allowed to crystallize for 15 hours at + 5 ° C.

The product was filtered, washed with n-butyl acetate (100 mL) and ethyl acetate (100 mL). It was dried in vacuo at 40 ° C for 24 hours.

Yield: 54.2 g (72%) of 6-ethoxycarbonyloxyethyl ester of 6- (D <-) -? -Amino-of-phenylacetamido) penicillanic acid, m.p. o 160-162 C. <d) and other properties corresponded to the authentic hydrochloride sample.

Compare reading example

Preparation of bacampicinin by the reaction of enamine-protected ampicillin 21 79115 with O <1 -chloronate without catalyst.

Step a) 6- (D (-) - N- (1-methocarbonylpropen-2-yl) - (- aminophenylacetamide), 7 penic acid 11 'acid 1'-ethochycarbonyl ter i.

6- (D - (-) - N- (1-methoxycarbonyl-1-yl-open-2-yl) -C 1 -aminophenylacetamide (penicillanic acid sodium salt <80%, 4.57 g, 0.008 mol) was dispersed in dry dimethylformamide < 15 ml) and with stirring and ice-cooling was added in o <-chlorodiethyl carbonate (1.53 g, 0.01 mol) dissolved in dry dimethylformamide (<7 ml). After 30 minutes, stirring was continued without cooling overnight. The reaction solution was poured into saturated sodium bicarbonate solution (175 mL) to give a white emulsion. This emulsion was diluted with H 2 O (125 mL) and extracted three times with ether. The combined ether phases were washed with water and saturated sodium chloride solution and dried. The ether solution was evaporated in vacuo to give 6-C6 (-) - N- (1-methoxycarbonylpropen-2-yl) -CX-aminophenyl-acetamide-7-isanoic acid 1'-ethocarbcarbonyl ethyl acetate <0.6 g). , with a purity of 70.4% <colorimetric analysis).

-1

The product had a strong IR absorption at 1780 cm and -1 1750 cm, indicating the presence of β-lactam and ester carbonyls. According to TLC (system: CH 2 Cl 2 / CHCl 3 / ethanol: 20/2/2) the Rf was 0.70.

Step b) 1'-Ethocarbonyl-1'-6- (D- (X-aminophenylacetamido) penicillanate hydrochloride.

22 791 1 5

Ethoxycarbonyloxyethyl ether of enamine-protected ampieillin, 1'-ethoxycarbonyloxyethyl-6 - D (-) - N- (1-methoxycarbonylpropen-2-yl) -o (-aminophenylacetamido] penicillanate <70 X, 0 , 6 g, 0.00072 mol) was dissolved in ethyl acetate (5 ml), water (5 ml) was added and then 2-N HCl was added dropwise while maintaining the pH at 2.5 with stirring for 15 minutes.

Petroleum ether (2 mL) was then added, and after stirring for 1 minute, the phases were separated. Sufficient NaCl was added to the aqueous layer to saturate the solution. After stirring for a few minutes, the precipitated oil was extracted with methylene chloride (1 x 10 mL, 1 x 5 mL). These extracts were combined, dried over dry MgSO 4, filtered and concentrated under reduced pressure to a volume of 0.5 mL.

Ether (3 mL) was then added and the resulting precipitate was stirred for 5 minutes. The product was filtered through a glass filter, washed with ether (2 x 1 mL) and dried overnight in vacuo to give a yellow-white powder (0.35 g, 79.9% <colorimetric analysis). The product was identical to an authentic sample of 1'-ethoxycarbonyl-oxyl-6- (D-CX-aminophenyl-acetamido) penicillanate hydrochloride, showing strong IR absorption at 1780-1750 cm due to β-lactam and ester carbonylation.

The NMR resonance of the product was identical to the authentic sample and by TLC (in the system CH 2 Cl 2 / CHCl 3 / ethanol: 20/2/2) the Rf was 0.46 <90%); 0.70 <10%), reference substance: 0.47.

The yield based on the starting material of step a) was 7%.

23 79115 Preparation of 1-ethoxycarbonyloxyethyl ester of 6- (D (-) - α-amino-α-phenylacetamido) -penicillan 5 For the preparation of 1-ethoxycarbonyloxyethyl 5-ethoxycarbonyloxyethyl ) -α-amino-α-phenylacetamido) -penicillanate with the formula: σ / S. ch3 / \ 3 CH - CO - NH - CH - CH C CI) III lx-3 NH2 CO - N-CH - C00 - CH - 0 - COOC2H5 ch3 15 For this purpose, the ampicillin ester is extremely extreme in the form of a therapeutic syndrome. the absorber is taken by oral administration and the skin is exposed to the ampicillin and the ampicillin.

20 The ester is isolated in the form of a bacampicillin and is treated with bacampicillin.

From this point onwards, the bacampicillin chloride (Jämför BE patent patents 772723) can be synthesized according to the following methods: A) i vatten i närvaro av sodium sodium bicarbonate.

30 The title 1-ethoxycarbonyloxyethyl ester of benzylpenicillin is reacted with a phenylacetyl ester via an iminochloride imino ether, and the 1-ethoxycarbonyloxyethyl ester of 6-aminopenicillanic acid is further isolated.

The genome is subsequently condensed into a system of products with D (-) - α-phenylglycine in the form of compounds I.

35 24 7 91 1 5 B) Preparation of 6- (D (-) - α-azido-α-phenylacetamido) -penicyl-lansyran with cx-chlorodiethylcarbonate and polar solution.

5 Derivatives according to formula I of the genome catalytic hydrogenation of 1-ethoxycarbonyloxyethyl ester of 6- (D (-) - α-azido-α-phenylacetamido) -penicillanyl.

10 This measure is based on the complexity of the use of non-essential materials and raw materials.

Därtill känner man genom FI-patentskriften 55203 ett förfa-15 rande fr frstställning av bacampicillin. Example 16b discloses a patent for the presence of 1-ethoxycarbonyloxyethyl ester of the bacampicillin genome with 6-aminopenicillans having the most envelope of the α-aminophenylate mixture. The bacampicillin chloride is added in an amount of 0.35 g, and 20 ml of 7% aminopenicillan sulfate are added.

Syftef. For example, upstream financing is required to be used for the production of active substances in the environment and industry for a total of 25 years. Because of the specific nature of the uptake, it is possible to use the same conditions for the production of bacampicillin under an ampicillin in the form of a backbone, which means that the use of these products and other products is not possible.

30

The reaction is further obtained for the preparation of 1-ethoxycarbonyloxyethyl esters of 6- (D - (-) - α-phenylacetamido) penicillans with the formula S CHo 35 / - \ \ ^ ^ \ -CH - CO - NH - CH - CH (I> \. / II CH3 NH2 CO - N-CH - COO - CH - O - COOC2H5 ch3 25 791 1 5 The genome of an ampicillin, which is in the form of an alkaline form, which reacts with an acetic acid to give a mixture of with formula 5 / - \ / 'S \ / CH3 10 \ Ί — CH - CO - NH - CH -CH2 (II> \ = / III | \ c „3

N. CO - N-CH - COOX

1 / \

R-C H

15 R-c \ S

C I 3 R

20 colors R1 is an alkyl group with 1-4 colaters, R2 is an alkyl group with 1-4 colaters, 25 R3 is an alkyl group with 1-4 colaters, an alkoxy group with 1-4 colaters or an amino group, and X is alkali metal, en jordal metal or organic base, which is used for the manufacture of certain by-products of formula II, with the addition of a bromodiethyl-30-formate

Br-CH-O-C00C 2H5 (HI) CH3 is a catalyst in the form of a mixture of esters with the formula 35 26 7 91 15 S CHq (/ \ _CH - CO - NH - CH - CH W / [j | | CH3 CO - N- · ΟΗ-000-ΟΗ-0-00002Η5 5 rc H CH3 2 II! RC .0 (IV) 13

R

color R1, R2 and R3 in the form of a solid, 10 and 10 after which the medium is determined by mild hydrolysis and that the medium is formed by the formulation of form I.

α-bromodiethylcarbonate is added to the reaction component in the form of a reaction. The preparation of ct-bromodietylkars-15 is isolated to a specific type and the addition of bacampicillin.

The reaction reaction is carried out in the second and third directions of the reaction catalyst.

20

The catalysts are then reacted with the reaction catalysts and the products are used and then reacted.

25 For the purposes of this invention, the following substances may be used as catalysts: quaternary ammonium salt, free tetrabutylammonium bromide, bromide or iodide from an alkali metal and cyclic ether.

30 Catalysts may be used in a variety of 0.005 to 0.10 mol per mol in the form of a third of three equimolar equations. In the case of the formulation of tetrabutylammonium bromide, it is obtained from 0,01 mol 0,10 mol per mol av föreningen III.

The group is selected from the group consisting of R1, R2 and R3: alkyl. * CH3, C2H5, n-C3H7, i-C3H7, n-C4H9 35 27 791 1 5 alkoxy (from R3): OCH3, OC2H5, OCH2CH2CH3, OCH (CH3) 2.0 (CHa) 3CH3.

Radikalen X är vald bland grupper som är väl kända inom 5 tekniken, till exempel

alkali metal: Na, K

alkali jordartsmetall: Ca, Mg 10 orgariisk bas: organic base based on the synthesis of penicilliners, till exempt tertiary ammonium group, triethylamine, ethylpiperidine and methylmorpholine.

15 In the form of a straight-chain form of an amylic group, the amino groups of the ampicillin and the 1-methoxycarbonyl-propen-2-yl group or the 1-ethoxycarbonyl-propen-2-yl group are used in the form of a straight-chain product. Black II sodium or potassium salts of N- (1-methoxycarbonyl-20-propen-2-yl) -penicillanic acid or N- (1-ethoxycarbonyl-propen-2-yl) -penicillanic acid (R1 = methyl) R2 = methyl, R3 = methoxy or ethoxy and X = Na or K).

Mellan products IV are stable and neutral or alkaline in medium, less than medium groups of amino acids in the head, preferably and selectively adjusted.

Groups of amino acids in the ampicillin can be used for up to 30 exempted groups of the same group as the GB patent patent 991586, and other groups of the group are as follows: in the technician.

For example, the use of ampicillin trihydric acid in the form of an acid-free form of anhydrous formulation, with the exception of Ν, Ν-dimethylformamide, is required after which the reaction of most of the (II) genomes is carried out with a derivative of 5 acetoacetate, with the exception of methyl acetoacetate; tatsats av en förestringskatalysator, heating with tetrabutylammonium bromide; 10 of the α-bromodiethylcarbonate account for the reaction of 1-ethoxycarbonyloxyethyl esters in ampicyclic form (IV); hydrolysis of the HCl group with HCl is carried out in an organic solution, excluding n-butyl acetate / water; in the case of bacampicillin vateklor genom mättning i vattenfas, to be exempted from sodium chloride and extraction with a warming solution, to be exempted from n-butyl acetate; Concentration of the reaction solution in the form of n-butyl acetate for crystallization of the product is complete, and the product is isolated by genomic filtration.

25 The form of a bacampicillic acid mixture having a maximum of one or more refinements can be practically used as a precautionary measure.

30 The use of a product or product which is the subject of the present invention does not in fact constitute a significant increase in the cost of the technical service.

35 I do not take any other ampicillin trihydrate with any of the excipients, and then the antibiotic is inverted in the form and on the other side.

29 791 1 5

Mellanproducten (II) can be obtained in the form of exemptions from GB patent 991586 and that a 95% genomic reaction with ampicillin trihydrates and 5 methyl or ethyl acetoacetates, 10% 50% of the stoichiometry, is obtained. en organisk bas eller ett alkalimetallkarbonat til exempel potassium carbonate.

Mellan products (II) are isolated and set aside for the reaction in a fast form. The reaction reaction is alternatively, after isolation of the product (II), using the same reaction method as the reaction for the main reaction (II).

Reactions for the reaction of ampicillin (II) with aprotic polish, such as N, N-dimethylacetamide, Ν, Ν-dimethylformamide, dimethoxyethane, dimethylsulfoxide, tetrahydrofuran or dioxane.

20 For this reaction, the temperature of the component and the blend are contacted at a temperature between 0 ° C and 60 ° C, warmed to 20 ° C and 30 ° C for 2 to 8 hours, warmed to 3 minutes.

25 Fertilization reactions after the addition of a bromodiethylcarbonate to a temperature of 15 ° C to 80 ° C, warm to 45 ° C to 55 ° C, under 1 time to 24 hours, warm to 5 10 timmar.

The reaction reaction is carried out by heating the organic solution with methylene chloride or acetone, dimethylacetamide, dimethylformamide and dimethylsulfoxide, or with an organic solvent. It is not possible to give an organic solution in the water.

35 An acetone is added to the reaction catalyst and acetone is used as a solution for the reaction reaction.

30 791 1 5

In this case, a warming agent is used for industrial purposes, isolated from the enrichment (IV) of the genome by reaction with water and after extraction with the addition of a warming solution which is not more than 5 blanks.

Acetate phase with the addition solution (0.2-0.3 N) of HCl is then fully hydrolyzed, the mixture is contacted at 2 to 8 times, warmed to 4-5 to 10 times at normal temperature.

The genome is then separated from the sodium chloride by separate reactions (I) into the water phase and in the form of the hydrochloride, which is added to the warming medium to give n-butyl acetate. 15

Concentration of the genome in an organic phase at a temperature of 40 ° C to a volume of ether, crystallization from the products of formula (I).

20 The crystals of the product are isolated by genomic filtration, drying and vacuuming.

The reaction reaction involves the addition of carboxylsyran to form II with α-bromodiethylcarbonate.

25

The reaction is carried out with a metal salt of a carboxylic acid and an alkylhydrogen or an arylalkyl halide under the action of an ester or a solution. It is possible for the emitters to have a specific temperature and reaction conditions and to reduce the temperature of the reaction temperature to 30 ° C. These synthetic compounds are synthetically reacted and reacted commercially with a color-coded and labile substance such as pyrethroider, prostaglandin, peptide, penicillin and cephalosporin.

GB-1 1,433,738 discloses the addition of a quaternary ammonium salt to a penicillin and a cephalosporin 35 3i 79115 for a metal rod having a penicillin and a cephalosporin.

Framställningen av det quaternära ammoniumsaltet av syran 5 kan vara tidskrävande och dyrbart. This dock, which is included in GB patent specification 1,443,738, is further disclosed as having a quaternary ammonium salt of a penicillin or a cephalosporin, after reacting with the genome of a carboxylic acid metal, containing 10 pellets. cephalosporins, which are reacted with alkyl- or arylalkylhalogens and are quaternized with ammonium salts, which are optionally salted with carbosyls.

15 For the purposes of the present invention, a portion of the ammonium salt of a quaternary ampoule is used in the form of an amylic acid in the form of an ampoule in the form of an amylic acid. .

In particular, the reaction of the amate with the addition of ethoxycarbonyloxyethyl esters of the ampicillin genomic reaction is carried out by means of a metal-containing ampicillin and the 25-bromodiethylcarbonate in the enrichment of the quaternary ammonium (which gives the carbons) än den stökiometriska mängden i förhällande account ampicillinet.

30 Up to 1% and 25% of the equivalent of quaternary ammonium salts are added with the addition of 1% and 10% of the equivalent of quaternary ammonium salts.

The quaternary ammonium salts from the carboxylic acid are heated by the genomic reaction to give the carboxylic acid and the quaternary ammonium salt from the face to give the carboxylic acid, 327 7 91 1 5 to the carboxylic acid, to the mineral salt to the salt salt, to the bromide.

The metal metal salt with carboxylic acid may be treated with an alkali metal and potassium, lithium, magnesium, magnesium, magnesium, magnesium, magnesium, lithium metal or lithium metal salt. Light quaternary ammonium salt with 10 carboxylic acids 15 Halogen halofider fluoride, chloride, bromide and iodide, heat activated fluoride or activated chloride or bromider or iodide.

The reaction reaction is preferably an aspect of the uptake of 20 can be disturbed or frost-free. Lämpliga lösningsmedel omfattar lägalifatiska alkoholer, lägalifatiska ketoner, lägalifatiska amider av myrsyra och dimetylsulfoxid. Alternatively, it is possible to obtain a solution of the halogenated ester, especially for the reaction reaction period.

This equimolar solution of the quaternary ammonium salt of the carboxylic acid and the ester corresponding to the α-bromodiethylcarbo-30 is obtained by reaction. Heat is added to a mixture of 5 and 100% of an ester of α-bromodiethyl carbonate for a shade equivalent of a carboxylic acid having the same value and a mixture of 20 and 60%.

α-Bromodiethylcarbonate with Formula III, which has been shown to be free from the genomic reaction with the addition of α- 35 33 7 911 5 chlorodiethyl carbonate and sodium bromide are all exempted for 1 week.

α-bromodiethylcarbonate with formula III can be obtained from 5 to the upper part A and B.

A. For the further preparation of A, the reaction comprises: 10 (a) a reaction with aldehydes of the formula CHaCHO (VI) and carbonyl bromide 15 20 Br CH3 - CH »0» C0 * Br (VIII) och; 25 (b) reacting α-bromo-bromoformate with Formula VIII and an alcohol with Formula C2H5-OH for the reaction of self-reacting α-bromodiethylcarbonate with Formula III.

30 For the purposes of this Regulation, the following measures are taken:

Br + C2H5OH Br

I I

35 CH3CHO + COBr2-> CH3-CH «OCO« Br-> CH3-CH «0« C0 «C2H5 + HBr α-bromo-bromoformate with formula VIII is used for the preparation.

34 79115

Reactions with aldehyde amine, CH3CHO, and carboxyl bromides at the same time as a catalyst in a catalyst exempt from tertiary aliphatic amine (a tertiary mixture of alkyl / aryl-amine or 5-tertiary aromatic amine), tertiary amide, substituents urea or thiourea, phosphorusureas, tertiary oxonium or sulfonium salt, or quaternary ammonium or phosphonium salt. Preferred catalysts for catalysts are pyridine, dimethylformamide, tetra-n-butylurea, hexamethylphosphoric triamide and benzyltrimethylammonium bromide.

The catalyst is heated to 0.05 to 0.55, the catalyst is 0.05 to 15 mol of aldehyde.

Reactions with aldehyde and carbonyl bromides in the heating medium and in the preparation are free from the use of both aromatic and aromatic flasks, such as toluene or halogens, flasks with dichloromethane, choletrachloride and chlorobenzene. The reaction is carried out with aldehyde and carbonyl bromide at a temperature of -40 to + 120 ° C, 0-40 ° C. The carbonyl bromides are treated with an alpehyde of about 10%, the enrichment of the enrichment is about 100%, the enrichment is about 50%.

Det as an intermediate erhällna α-bromo-bromoformiatet som of the formula VIII is obtained in step (a) of the method A behöver 30 ej isolating upstream the reaction is with the alcohols C2H5OH och det is in the själva verket i allmänhet lämpligt order not göra properties. Preferably, the preferred form of the reaction is in the form of a mixture of carbonyl bromide, which is exempted from the genome uptake under 35 reductions or the genome spindles are quenched. These α-bromo-bromoformates are then reacted with a reagent with an alcohol. Reactions with warming up the genome uptake of 35 79 1 1 5 bleaching under the offspring utilizing upstream or off the genome uptake of the tertiary bases with bleaching and, in particular, uptake, uptake. Optionally, the restatatalyst from the step (a) or complex of carbonyl bromide is synthesized and then the inverted head is reacted with the reaction and can fall to the ground.

The α-bromocarbonate is isolated in 10 parts of the reaction genome as a destination under reducing conditions.

For the purposes of Articles 2 and 3.

15 B. Det andra förfarandet, förfarande B, för framställning av α-bromodietylkarbonat beskrives i det feljande. Method B exemptions and exemptions 4.

For the purpose of the reaction of the a-20 bromodiethyl carbonate with the modification of the reaction, the genomic reaction is preferably carried out with alkyl chlorides or arylalkyl chlorides (or, for example, with the addition of an alkyl group) and an alkali metal broth. en brom-respect-25 ve iodine substituent; or a genomic reaction with an alkyl bromide or an arylalkyl bromide (or an aromatic alkyl bromide) with an alkali metal iodide for the addition of bromine substituents with an iodine substituent.

30 Finkelstein reactions are carried out by the reaction of iodide with lower reactants and bromide with some reactive chlorides. In each fall, a catalytic game of alkali metal bromide or iodine and a further reactive reaction is shown. For the purpose of the reaction, a total of 35 reactants with a different substrate of alkali metal bromide or iodine react and react with such reactants.

36 791 1 5

In this case, optionally substituted alkyl chlorides or arylalkyl chlorides are reacted and specially treated with alpha-chlorine and α-chlorocarbonate reactions, which may have a color of chlorine at the same time as the carbon monoxide. or other groups in the group C (O) -0-. In order to exempt the α-chlorocarbonate and α-chlorodiethylcarbonate from other products of the ethoxycarbonyloxy-ethyl ester with 6-aminopenicillansyra and the penicillin, it can be used as an additive.

This problem can be caused by the reaction of the genome under the action of a solution system with 2 packets, which can be used in the form of water and with the other side of the packing system of 15 or more of the organic feed system.

The lamps with a mixture of organic organic solvents may be added up to a maximum of 20 halogen, with the exception of halogenated paraffin or dichloromethane; och aromatiska kolväten säsom toluen. Lämpliga fasöverföringskatalysatorer omfattar quaternära ammonium salt-ter, tiliom cetyltrimethylammonium bromide och tetra-n-butylammoniumvätesulfat. Alka-25 1imetällbromiden kan til exempel utgöras av natrium-, potassium- eller lithium bromide, varvid lithium bromide föredrages.

In the case of B-rings with a list of chlorodiethyl carbonates in the form of: 30

Cl 0 CH3-CH-0-C-0-C2H5 (IX) 35 i and the feed system with the same water, and with the aid of a bleaching organic organic feed, react with the time bromide of the form 37 37115 R-Br (X) color R is an alkali metal in the form of Na, K and Li, for 5 fractions of the formulation:

Br 0

I II

CH3-CH-O-C-O-C2H5 (III)

15 The same method is used to prepare a solution of lithium bromide in a conventional manner by means of a conventional Finkel-Stein reaction (detached from organic halogen production system and its own), exempted from halogen generation and α- klorokarbonat. The exemplary exemption of 20 persons is exempted 5.

Lämpliga lösningsmedel för ett sädant förfarande omfattar lägalifatiska alkoholer, lägalifatiska ketoner, lägalifatis-ka etrar och lägalifatiska amider av myrsyra.

25 Följande exempel belyser uppfinningen. Exemplary 1-6 internal frameworks in the form of materials III and exempted 7 internal fractions are included in the uptake.

30 Exempel 1

Framställning av α-bromodietylcarbonat acetone

NaBr + CI-CH-OCOOC2H5-> Br-CH-OCOOCaHs + NaCl

35 I I

ch3 ch3

Sodium bromide (102.9 g) was added to acetone (600 ml) and the reaction was reacted with 2-3 α-chlorodiethyl carbonate (152.6 g) at room temperature (20-25 ° C) to give 100 ml of acetone. Bland-ningen concentrates därefter under vacuum vid slur tempera- 38 791 1 5 tur, max. 35 ° C, tills en halvfast mass erhällits. Reactions were obtained after the reaction with H 2 O / ethyl ether. Vatten-fasen separerades och extraherades därefter tvä gänger med 400 ml etyleter.

5

The same organic mixture of which is α-bromo-diethyl carbonate with 800 ml of H2O 10 1 000 ml up to 1% strength with sodium metabisulphate 1 000 ml with sodium chloride

The organic phase is pierced with Mg sulfate and concentrated under vacuum at a temperature of max. 35 ° C, 15 varvid titelprodukten erhölls (60%) i form av en vätska som frän början var färglös eller svagt gulbrun. The provisions of this Directive do not apply to exemptions.

Example 2 20 ml of acetaldehyde (44 g; 1 mol), cholestetrachloride (300 ml) and carbonyl bromide (235 g; 1.25 mol) are cooled to 0 ° C and the temperature is reduced to the temperature of the genome. from 1 to 3 of pyridine (11.9 g; 0.15 mol).

25

The temperature is maintained at room temperature and up to 50 ° C and at a temperature below the temperature of 3 hours.

The reaction mixture was reduced under reduced pressure at 50 ° C to give a solid and an oil (ethanol (92 g; 2 mol)) which was stirred and stirred under citrate. After uptake under ether and another 2 times, the mixture was stirred with ethanol in vacuo and ether-35 times with water (100 ml) and methylene chloride (200 ml).

39 7 911 5

Separation from an organic skeleton and fractional distillation to ethyl ethyl α-bromoethyl carbonate (130 g; 66%) at a total temperature of 90-92 ° C at a temperature of 45 mm Hg and less than identical to authentic samples .

5

Exempel 3

Bleaching of acetaldehyde (44 g; 1 mol), dichloromethane (300 ml) and hexamethylphosphorus pyratriamid (17.9 g; 0.1 mol) was cooled to -10 ° C and a solution of carbonyl-10 bromide (207 g; 1 , 1 mol) under a temperature of 4 ° C at 10 ° C.

Blandningen upphettades därefter under svagt äterflöde (cirka 40 ° C) i 4 timmar. The mixture was stirred at room temperature until 15 ml of ethanol (69 g; 1.5 mol) was added under 1 hour and at least 1 hour.

The destination fraction of the desired mixture was obtained directly from ethyl α-bromoethyl carbonate (114 g; 58% yield).

20

However, ethyl α-bromoethyl carbonate can be authenticated by genomic analysis and can be synthesized.

25 Diethyl carbonate (118 g; 1.0 mol) is obtained and refluxed at 110 ° C to 120 ° C and heated with a tungsten lamp at 150 W. Bromine (96 g? 0.6 mol) is added dropwise under 3 times. -4 timmar och med med sädan hastighet att blandningen ej antog en djupare färg än blekt orange.

The bromine was stirred at room temperature and stirred with sodium bicarbonate (20 g).

The destination and fractionation are then obtained by blending with 35 g of authentic ethyl α-bromoethyl carbonate (84.2 g; 70% yield) at a total temperature of 87-88 ° C to a temperature of 40 mm Hg.

40 791 1 5

Exempel 4

The lithium bromide (43 g; 0.5 mol), ethyl α-chloroethyl carbonate (15.3 g; 0.1 mol), dichloromethane (100 ml) and ethyl trimethylammonium bromide (1 ml) were added. , 5 g) of 5 to 24 rum. Water was added dropwise and stirred with lithium bromide (26 g; 0.3 mol) in water (40 ml) with acetyltrimethylammonium bromide (1 g). After 24 hours at room temperature, the mixture was separated at 35 ° C, separated and vacuum distilled to give a further fractionation fraction of the residue, ethyl α-bromoethyl carbonate (15.0 g; 76% yield). en kokpunkt av 90-92 ° C vid ett tryck av 35 mm Hg.

15 Funnet: C 30.7 H 4.8 Br 40.1%

Reaction: C 30.5 H 4.6 Br 40.6% NMR spectrum visade Toppar: 1.2-1.6 (3H, triplet) -CH 2 • CH 3 2 O 2.0-2.2 (3H, doublet) ) -CH »CH3 4.1-4.5 (2H, quartet) -CH =« CH3 6.5-6.8 (1H, quartet) -CH »CH3

Exempel 5 Lithium bromide (17.4 g; 0.2 mol) was dissolved in dimethylformamide (150 ml) and stirred at room temperature. Ethyl α-chloroethyl carbonate (30.5 g; 0.2 mol) was added and stirred at room temperature for 24 minutes. The lithium chloride is filtered off and the vacuum distillate is filtered off and then refluxed with ethyl α-bromoethyl carbonate to give 76% of the basic ethyl α-chloroethyl carbonate.

Example 6 35 The addition of ethyl and α-bromoethyl carbonates is authentic to the genome and the synthesis is as follows: 4i 79115

Bleaching of diethyl carbonate (35 g; 0.3 mol) into coltetra chloride (50 ml) and α-azoisobutyronitrile (AIBN) (0.1 g) was added dropwise to ether and dibromodimethylhydantoin (28.6 g; , 1 mol) was added to a portion under 5 and 8 times 8 times with the addition of AIBN (8 x 0.05 g). Härvid tillses att fritt Brom ej ansamlas i reaktionsblandningen. The reaction mixture was then bleached for fractionation to the destination in vacuo to give ethyl α-bromoethyl carbonate (32.3 10 g; 82% yield) which was then identical to the products of Example 4 and 5.

Exempel 7 25.08 g (0.181 mol) of a powdered powder of potassium carbonate-15-free suspension in 200 ml of Ν, Ν-dimethylacetoxide and 32.4 ml (0.3 mol) of methyl acetoacetate and 60.4 g (0.15 mol) of ampicillin trihydrat tillsättes.

The mixture is stirred at 5 to 20 ° C; After 20 ml, 46.1 g (0.234 mol) of bromodiethyl carbonate, 6 g (0.02 mol) of tetrabutylammonium bromide and 100 ml of N, N-dimethylacetamide are obtained.

Blandningen up to 10 ° C at 40-42 ° C; The reaction mass is mixed with 25 ml of water and 400 ml of n-butyl acetate.

Water is added and the mixture is extracted with 100 ml of n-butyl acetate.

30 Of the organic organic compounds, a solution of 100 ml of water is used. 150 ml of N HCl and 370 ml of water are added to the organic phase; the temperature is below 22-23 ° C at 4 ° C.

35 Watten pellets and organic pellets with 100 ml wattage.

42 791 1 5

For example, water at a pH of up to 10% up to 10% with Na2CC> 3, after which the mixture is filtered and filtered.

5 300 ml of n-butyl acetate and 80 g of sodium chloride are filtered off with water.

The organic phase is separated and the aqueous phase is extracted with 200 ml of n-butyl acetate.

10

The n-butyl acetate mixture is concentrated at 40 ° C to a volume of about 300 ml. The product is crystallized at 15 ° C at + 5 ° C.

The filtrate was taken up in n-butyl acetate (100 ml) and ethyl acetate (100 ml). The vacuum tube is heated to 40 ° C for 24 hours.

Yield: 54.2 g (72%) of 1-ethoxycarbonyloxyethyl ester of 6- (D (-) - α-amino-α-phenylacetamido) -penicillanate with a melting point of 20 DEG-160 DEG C. överensstämmer med det authenticiska vätekloridprovet.

Jämförelseexempel

Framställning av bacampicillin genomeaction mellan ena-25 minskyddat ampicillin och α-chlorordietylcarbonat utan närvaro av katalysator

Step a) 1'-Ethoxycarbonylloxyethyl ester 6 - ((Df -) - N- (1-methoxycarbonylpropene-2-yl) -α-aminophenylacetamidolpenicillan

Sodium salt of 6- [D (-) - N- (1-methoxycarbonylpropen-2-yl) -α-aminophenylacetamido] penicillan syrup (80%, 4.57 g, 0.008 mol) was dispersed in dimethylformamide (15 ml) and under a mixture. The reaction mixture was treated with α-chlorodiethylcarbonate 35 (1.53 g, 0.01 mol) and treated with dimethylformamide (7 ml).

After 30 minutes for a while after each night. The reaction reaction is carried out with sodium bicarbonate solution (175 ml), colorless and emulsion-free, Is, 43 791 1 5

The emulsion was dissolved in H 2 O (125 mL) and extracted with ether. The combined ethers of the sodium hydroxide solution and the sodium hydroxide solution are added. Vacuum treatment of ether to give 1'-ethoxycarbonyl-5-ethyl ester of 6- [D (-) - N- (1-methoxycarbonylpropen-2-yl) -α-aminophenylacetamido] penicillan (0.6 g) with a crude gradient of 70 .4% (colorimetric analysis).

The products are obtained by IR absorption between 1 780 cm-1 and octane at 1 750 cm-1, with a total of β-lactam and ester carbonylers. TLC (system: CH 2 Cl 2 / CHCl 3 / ethanol: 20/2/2) var Rf: 0.70.

Step b) 1'-Ethoxycarbonylloxyethyl-6- (D-α-aminophenylacetamido) -15 penicillan hydrochloride

The enamine-protected ethoxycarbonyloxyethyl ester of ampicillin, 1'-ethoxycarbonyloxyethyl-6- [D (-) - N- (1-methoxycarbonylpropen-2-yl) -α-aminophenylacetamido] penicillanate (70%, 0.6 g , 20 0.00072 mol) was added dropwise to ethyl acetate (5 ml), water (5 ml) was added and 2-N HCl was added dropwise, and the pH was adjusted to 2.5 over 15 minutes.

Petroleum ether (2 ml) was added to the residue and then stirred for 1 to 25 minutes. Then, with NaCl, the water is then skimmed to the solution. After this minute, the mixture was extracted with oil with methylene chloride (1 x 10 mL, 1x5 mL). The extract was combined with MgSO 4, filtered and concentrated under reduced pressure to 0.5 mL.

Ether (3 mL) was added to the residue and the mixture was stirred for 5 minutes. Products in filter head glass filter, etching with ether (2 x 1 ml) and passing over a vacuum of 35 g, gives a colorless powder, 0.35 g, gives a shear color of 79.9% (colorimetric analysis). The product can be identically treated with 1'-ethoxycarbonyloxyethyl 6- (Da-aminophenylacetamido) penicillan hydrochloride up to a total of 1 780 to 1750 cm-1. lactam and ester carbonylers.

The NMR resonance of the product was identical to that of an authentic 5 and enriched TLC (CH 2 Cl 2 / CHCl 3 / ethanol system: 20/2/2) var Rf: 0.46 (90%); 0.70 (10%) reference substance: 0.47.

Utbyte, räknat pä utgängsmateriälet i steg a): 7%.

10 15 20

Claims (6)

A process for the preparation of the 1-ethoxycarbonyloxyethyl ester of 6- (D - (-) -ct-amino-ct-phenylacetamido) penicillanic acid of the formula, __ S. CH // -NH-CH - CH C (i) W | \ CH I 3 NH CO - N- CH - COO - CH - O - COOC H 2 CH 5 CH 3 by reacting ampicillin, preferably in the form of an alkali salt, with a reactive derivative of acetoacetic acid to give the corresponding enamine of the formula / -v CH 2 CO - N - CH - COOX 1 + R -c H 2. ii IR _C O xc 2 I 3 R wherein is an alkyl group of 1-4 carbon atoms, 2 R is hydrogen or an alkyl group of 1-4 carbon atoms, 3 R is an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms or an amino group, and X is an alkali metal, an alkaline earth metal or an organic base, characterized in that the obtained intermediate of formula II is reacted with α-bromo diethyl carbonate of formula 49 79 1 1 5 Br-CH-O-COOC H (III) In CH 3 in the presence of a catalyst sator for forming the corresponding ester of the formula ^ CH3O 'V-CH - CO - NH - CH - CH C ν = λ | | | | vch3 N CO - N -CH -COO -CH-O-COOC H \ / \ I 2 5 R - C H CH. Wherein R, R and R are as defined above and thereafter a mild hydrolysis is carried out in a known manner in an acidic medium to form the compound of the formula IN. Process according to claim 1, characterized in that the alkali salt of ampicillin is obtained by converting ampicillin trihydrate in a known manner in a polar solvent, preferably in N, N-dimethylformamide. Process according to claim 1, characterized in that the formation of the enamine (II) is carried out by reacting the alkali salt of ampicillin with an alkyl acetoacetate, preferably methyl or ethyl acetoacetate, in an amount which is preferably 10-50% greater than the stoichiometric amount, in a aprotic polar solvent at a temperature between 0 ° and 60 ° C for 2-8 hours, preferably in the presence of an organic base or an alkali carbonate. Process according to claim 1, characterized in that the esterification reaction of the enamine (II) is carried out by adding in the reaction mixture α-bromo diethyl carbonate, wherein